B-cell Acute Lymphocytic Leukemia (B-ALL) is the most common cancer in children. While great progress has been made in the development of treatments for B-ALL, approximately 20% of patients still fail to respond to standard therapies. Thus, studies that enhance our understanding of the basic biology behind these aggressive sub-types of B-ALL remain important; as such research could plausibly identify effective therapies for patients who have failed standard treatment. The present proposal is based on the observation that a specific sub-type of aggressive B-ALL (low hypodiploid B-ALL) may be derived from very primitive precursors of B-cells. The first two aims proposed will test the hypothesis that these tumors not only derive from primitive precursors, but also retain the activity of specific biological pathways expressed in this cell type, specifically responsiveness t signals from the pre-B cell receptor. If so, then drugs recently developed for mature B cell lymphomas (which typically affect the elderly) may be applicable in this small subset of B-ALL. Thus, the third aim of the proposal is to develop laboratory methods by which to test whether these tumors are especially sensitive to the drug class in question (fostamatinib and ibrutinib).